RESUMEN
BACKGROUND: Members of the α-thymosin family have long been studied for their immunostimulating properties. Among them, the danger-associated molecular patterns (DAMPs) prothymosin α (proTα) and its C-terminal decapeptide proTα(100-109) have been shown to act as immunomodulators in vitro, due to their ability to promote T helper type 1 (Th1) responses. Recently, we verified these findings in vivo, showing that both proTα and proTα(100-109) enhance antitumor-reactive T cell-mediated responses. METHODS: In view of the eventual use of proTα and proTα(100-109) in humans, we investigated their safety profile in silico, in human leukocytes and cancer cell lines in vitro, and in immunocompetent mice in vivo, in comparison to the proTα derivative thymosin alpha 1 (Τα1), a 28-mer peptide extensively studied for its safety in clinical trials. RESULTS: In silico prediction via computational tools showed that all three peptide sequences likely are non-toxic or do not induce allergic regions. In vitro, pro- Tα, proTα(100-109) and Tα1 did not affect the viability of human cancer cell lines and healthy donor-derived leukocytes, did not promote apoptosis or alter cell cycle distribution. Furthermore, mice injected with proTα, proTα(100-109) and Tα1 at doses equivalent to the suggested dose regimen of Tα1 in humans, did not show signs of acute toxicity, whereas proTα and proTα(100-109) increased the levels of proinflammatory and Th1- type cytokines in their peripheral blood. CONCLUSION: Our preliminary findings suggest that proTα and proTα(100-109), even at high concentrations, are non-toxic in vitro and in an acute toxicity model in vivo; moreover, we show that the two peptides retain their immunomodulatory properties in vivo and, eventually, could be considered for therapeutic use in humans.
Asunto(s)
Neoplasias , Timosina , Humanos , Ratones , Animales , Timosina/toxicidad , Péptidos/uso terapéutico , Citocinas , Factores Inmunológicos/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
AIM: Rasagiline mesylate (N-propargyl-1 (R)-aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase-B with cardioprotective and anti-apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery. METHODS AND RESULTS: RG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end-systolic and diastolic dimensions and preserved fractional shortening in RG-treated compared with normal saline group at 28 days post-MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non-infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress. CONCLUSIONS: Our study demonstrates a positive effect of RG in the post-MI period with a significant attenuation in cardiac remodelling.